Macrophages are important cells in the host resistance to fungal infections, and fungal recognition by macrophages triggers phagocytosis, intracellular killing, induction of inflammatory cytokines and chemokines, and initiation of the adaptive immune response. All the macrophage receptors that mediate binding and engulfment of fungal pathogens and the signaling pathways triggered by fungal pathogens that regulate anti-fungal immunity are not fully understood. Our long-term goals are to identify the molecular mechanisms of macrophage activation by fungal pathogens and the impact of these pathways on fungal pathogenesis. Toll-like receptors (TLRs) are a class of pattern recognition receptors (PRRs) that mediate the recognition of many microbial products, and signaling through TLRs leads to the production of inflammatory mediators. We hypothesize that members of the scavenger receptor family, a class of PRRs that direct the uptake and clearance of polyanionic ligands of both pathogen and self origin, collaborate with TLRs in the recognition of fungal pathogens. This hypothesis is based on preliminary findings that co-expression of SCARF1 or CD36 with TLR2/6 in HEK293 cells results in enhanced NF:B activation in response to Cryptococcus neoformans stimulation. In addition, we found that macrophages deficient for SCARF1, CD36, or TLR2 expression had a reduced capacity to produce cytokines in response to C. neoformans stimulation. In this proposal, we will define the mechanisms of anti-fungal immunity mediated by SCARF1 and CD36 in vitro and in vivo. Specifically, we will (1) determine the role of SCARF1 and CD36 in facilitating TLR signaling by fungal pathogens, (2) Determine the contribution of SCARF1, CD36, and TLR2 signaling in fungal pathogenesis in mice, and (3) Determine whether SCARF1 and CD36 expression is required for dendritic cell maturation by fungal pathogens. Identifying the receptors and signaling pathways involved in regulating macrophage inflammatory responses to fungal pathogens will provide valuable insight into the role of these cells in fungal pathogenesis and possibly serve as therapeutic targets for novel drug design. PUBLIC HEALTH RELEVANCE: There is a pressing need for the development of new anti-fungal drugs to combat the increasing number of fungal infections and the increase in drug-resistant fungal species. In fungal infections, the inflammatory response is mediated by macrophages that are critical in the binding, engulfment, and killing of fungal cells. Identifying the receptors and signaling pathways involved in regulating macrophage inflammatory responses to fungal pathogens will provide valuable insight into the role of these cells in fungal pathogenesis and possibly serve as therapeutic targets for novel drug design.